Notch signaling has shown to play a key role in several kidney diseases, associated with glomerulosclerosis and podocyte apoptosis. However, its role in Human Immunodeficiency Virus Associated Nephropathy (HIVAN) which presents with collapsing variant of glomerulosclerosis, focal segmental glomerulosclerosis, and podocyte/parietal cell proliferation is not known. We used HIVAN patients and rodent models of HIVAN that express seven of the nine HIV genes and phenocopy most characteristics of HIVAN. We show that in contrast to other glomerular diseases, where Notch 1 and Notch2 receptor activation is predominant, Notch 4 pathway appeared to be most predominating in HIVAN. We found activated Notch4 expressed and elevated in podocytes, parietal epithelial cells and tubular epithelium. Pharmacological inhibition of Notch pathway in vivo ameliorated the disease progression in the Tg26 mice. Moreover podocyte proliferation induced by HIV proteins was inhibited by Notch inhibitors. These studies suggest that aberrant Notch signaling, contributes to the pathogenesis of HIVAN. In the first aim, we will determine the effects of podocyte and parietal cell specific genetic inhibition of Notch signaling on disease severity in Tg26 mice. In the second aim, we will perform in vitro studies from podocytes derived from Tg26 mice to determine the effect of Notch inhibition on podocyte proliferation, differentiation and apoptosis. We will also use parietal epithelial cells and podocytes to evaluate the possibility of interaction of Notch proteins with HIV-1 proteins. Finally in the third aim, we will genetically knockdown Notch4 in Tg26 mice and the possibility of disease prevention will be determined. These studies will provide: 1) a mechanism of Notch activation by HIV-1 and 2) a therapeutic platform to test Notch inhibitors in HIVAN patients.